Sustanined-release pharmaceutical composition for lung administration

ABSTRACT

The present invention provides a sustained-release pharmaceutical composition containing a pharmacologically active substance, the pharmaceutical composition being able to control the pulmonary absorption of the pharmacologically active substance and produce prolonged pharmacological effects when administered via the pulmonary route. The invention provides a pharmaceutical composition containing carrageenan and a pharmacologically active substance that can be administered via the lungs, a production method and use thereof.

TECHNICAL FIELD

The present invention relates to a sustained-release pharmaceuticalcomposition that can be administered pulmonarily, and a productionmethod and use thereof.

BACKGROUND OF THE INVENTION

Generally, pulmonary absorption of drugs is faster than gastrointestinalabsorption and it is known that the smaller the molecular weight and thehigher the oil/water partition coefficient, the faster the absorption.In recent years, it has been reported that comparatively fast absorptionrates can be achieved even with water-soluble drugs and macromoleculardrugs. Therefore, pulmonary absorption is attracting attention as a newadministration route for drugs expected to exhibit systemic effects suchas insulin, calcitonin and like biologically active peptides.

However, some drugs, even administered in trace amounts, have a strongaction. If pulmonary absorption is too rapid, the drug concentration inplasma rapidly increases and may produce adverse side effects.Furthermore, although pulmonary administration has the advantages ofallowing good absorption and immediate effectiveness, it is difficult toprolong the therapeutic effects of drugs and there is also the problemof patient inconvenience because some drugs require frequentadministration.

A means for prolonging the pharmacological effects of inhalants is, forexample, the use of a liposome preparation as a liquid inhalant asdescribed in U.S. Pat. No. 5,192,528. However, liposomes are generallyunstable and difficult to preserve stably at room temperature for a longperiod of time.

Therefore, a stable sustained-release pharmaceutical composition forpulmonary administration that allows pharmacologically active substancesto be absorbed in the lungs at a controlled rate and exhibits prolongedpharmacological effects has been in great demand.

Japanese Unexamined Patent Publication No. 36233/1992 discloses asustained-release drug prepared by producing microspheres from anaqueous solution of a water-soluble polymer containing a physiologicallyactive substance and encapsulating the polymer in a hydrophobic,biodegradable and bioabsorbable polymer. As examples of suchwater-soluble macromolecular substance, the publication mentions sodiumalginate, gelatin, carrageenan, etc. However, there is no mention aboutthe administration of this sustained-release drug via the pulmonaryroute.

DISCLOSURE OF THE INVENTION

An object of the invention is to provide a sustained-releasepharmaceutical composition containing a pharmacologically activesubstance, the pharmaceutical composition being able to control thepulmonary absorption of the pharmacologically active substance andproduce prolonged pharmacological effects when administered via thepulmonary route.

The present inventors carried out intensive research to solve theproblem in the background art and found that addition of carrageenan toa pharmacologically active substance that can be administered via thelungs can solve the problem. The inventors carried out further intensiveresearch based on this finding and thereby accomplished the invention.

The present invention thus provides the following:

Item 1. A sustained-release pharmaceutical composition for pulmonaryadministration comprising carrageenan and a pharmacologically activesubstance that can be administered via the lungs.

Item 2. A pharmaceutical composition according to item 1, wherein thecarrageenan is at least one member selected from the group consisting ofkappa-carrageenan, iota-carrageenan and lambda-carrageenan.

Item 3. A pharmaceutical composition according to item 1, wherein thepharmacologically active substance is at least one member selected fromthe group consisting of anticholinergic drugs, β2 stimulants, steroids,antiasthmatic drugs, antiallergic drugs, antiinflammatory drugs,antibacterial drugs, antifungal drugs, anti-influenza virus drugs,peptide drugs, antitumor drugs and vitamins.

Item 4. A pharmaceutical composition according to item 1, whereincarrageenan is present in an amount of about 0.001 to 10⁷ wt. % relativeto the pharmacologically active substance.

Item 5. A pharmaceutical composition according to item 1, whereincarrageenan mainly comprising iota-carrageenan is present in an amountof about 0.01 to 10⁵ wt. % relative to the pharmacologically activesubstance and the pharmacologically active substance is one memberselected from the group consisting of β2 stimulants, antiasthmatic drugsand steroids.

Item 6. A pharmaceutical composition according to item 1, which is inthe form of a powder having a mean particle diameter of about 0.1 to 20μm.

Item 7. A process for preparing a sustained release pharmaceuticalcomposition in the form of a powder for pulmonary administration, theprocess comprising drying an aqueous solution or aqueous dispersioncontaining a pharmacologically active substance that can be administeredvia the lungs and carrageenan, followed by pulverization, or comprisingspray drying the solution or dispersion.

Item 8. An inhalant comprising the pharmaceutical composition accordingto any one of items 1 to 6.

Item 9. An aerosol comprising the pharmaceutical composition accordingto any one of items 1 to 6, a propellant and an aerosol container.

Item 10. An aerosol according to item 9, wherein relative to thepharmacologically active substance, carrageenan is present in an amountof about 0.01 to 10⁴ wt. %, and propellant is present in an amount ofabout 10² to 10⁷ wt. %.

Item 11. An aerosol according to item 9, which further comprises atleast one member selected from the group consisting of solvents anddispersants.

Item 12. An aerosol according to item 11, wherein relative to thepharmacologically active substance, the solvent is present in an amountof about 0 to 10⁶ wt. %, and the dispersant is present in an amount ofabout 0 to 10³.

Item 13. A method for administering to a patient a pharmacologicallyactive substance that can be administered via the lungs, the methodcomprising administering an effective amount of a pharmacologicallyactive substance in combination with carrageenan to the patient via thepulmonary route.

Item 14. A method for sustainedly releasing a pharmacologically activesubstance in the lungs, comprising administering via the lungs aneffective amount of a pharmaceutical composition containing thepharmacologically active substance and carrageenan.

Item 15. Use of carrageenan for preparing a sustained-releasepharmaceutical composition for pulmonary administration of apharmacologically active substance.

Item 16. Use of carrageenan for sustainedly releasing apharmacologically active substance in the lungs by administering via thelungs an effective amount of a pharmaceutical composition containing thepharmacologically active substance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the change in serum theophylline concentrationafter intratracheal and intravenous administrations of solution A usedin Test Example 1 (n=4, mean±S.D.).

FIG. 2 is a graph showing the change in serum theophylline concentrationafter intratracheal administration of solutions A to D used in TestExample 1 (n=4, mean±S.D.).

DETAILED DESCRIPTION OF THE INVENTION

The sustained-release pharmaceutical composition for pulmonaryadministration (hereinafter also referred to simply as “pharmaceuticalcomposition”) of the invention is described below in detail.

The pharmaceutical composition of the invention comprises apharmacologically active substance that can be administered via thelungs (hereinafter also referred to simply as “pharmacologically activesubstance”) and carrageenan. The composition is characterized bycontaining carrageenan as a means for controlling the absorption rate ofthe pharmacologically active substance in the lungs.

The pharmacologically active substance used in the invention is notparticularly limited so long as the substance exhibits pharmacologicaleffects when administered to, for example, mammals via the pulmonaryroute. A wide variety of known substances that act locally, for example,on the trachea, bronchi, lungs or the like, or act on the entire bodycan be used. Examples of such pharmacologically active substancesinclude central nervous system drugs, peripheral nervous system drugs,cardiovascular drugs, drugs for the digestive organs, antibiotics,chemotherapeutic drugs and the like. Specific examples includeanticholinergic drugs (e.g., ipratropium bromide, flutropium bromide,oxitropium bromide, thiotropium bromide), β2 stimulants (e.g.,procaterol, fenoterol, salbutamol, formoterol, salmeterol), steroids(e.g., beclomethasone, fluticasone, budesonide), antiasthmatic drugs(e.g., theophylline, aminophylline, ozagrel), antiallergic drugs (e.g.,ketotifen, terfenadine, azelastine, epinastine), antiinflammatory drugs(e.g., diclofenac sodium, ibuprofen, indomethacin), antibacterial drugs(e.g., cefixime, cefdinir, ofloxacin, tosufloxacin), antifungal drugs(e.g., fluconazole, itraconazole), anti-influenza virus drugs (e.g.,zanamivir, oseltamivir, amantadine), peptide drugs (e.g., insulin,calcitonin), antitumor drugs (e.g., fluorouracil, gefitinib), vitamintablets (e.g., alfacalcidol, mecobalamin) and the like; and derivativesthereof. Such pharmacologically active substances can be used alone oras a mixture of at least two members selected from the above group. Suchpharmacologically active substances include salts (e.g., hydrochlorides)and prodrugs thereof.

Carrageenan used in the invention is a macromolecule having a molecularweight of 100,000 to 500,000 and obtained by extracting with water redalgae such as Gigartinaceae Gigartina and Chondrus and SolieriaceaeEucheuma. Carrageenan is a polysaccharide mainly comprising galactoseand 3,6-anhydrogalactose. As shown below, carrageenan has sulfatehemiester moieties in the unit structure and may be classified into fivetypes, i.e., kappa(κ)-carrageenan, iota(ι)-carrageenan,lambda(λ)-carrageenan, mu(μ)-carrageenan and eta(η)-carrageenan,according to the content of sulfate hemiester moieties. In theinvention, the five types of carrageenan can be used singly or incombination. The mixing ratio can be suitably selected according to thepurpose of use. Of the above five types of carrageenan,kappa-carrageenan, iota-carrageenan and lambda-carrageenan arepreferable. Especially preferable is carrageenan mainly comprisingiota-carrageenan. iota-carrageenan is particularly suitable for use.

The pharmaceutical composition of the invention contains the abovepharmacologically active substance and carrageenan. When the compositionis administered via the pulmonary route, the pharmacologically activesubstance is retained in the lungs by the action of carrageenan andgradually and sustainedly released. Therefore, the pulmonary absorptionrate of the pharmacologically active substance can be controlled and theplasma pharmacologically active substance concentration is maintainedsustainedly and stably. Moreover, the pharmaceutical composition of theinvention has good storage stability.

The pharmaceutical composition of the invention may contain, in additionto the pharmacologically active substance and carrageenan, additives asdescribed below. Such additives are not particularly limited and may beany additives used in the preparation of drugs. Specific examplesthereof include solid excipients such as refined sugar, lactose,glucose, fructose, sucrose, mannitol, sorbitol, arabinose, xylitol,dextrose and the like; liquid excipients such as propylene glycol andlike inert liquids; binders such as methylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycols,refined sugar and the like; lubricants such as magnesium stearate, lightanhydrous silicic acid, talc, sodium lauryl sulfate and the like;preservatives such as sodium benzoate, sodium hydrogen sulfite, methylparaben, propyl paraben and the like; stabilizers such as citric acid,sodium citrate and the like; dispersants such as methylcellulose,polyvinylpyrrolidone, lecithin, sorbitan trioleate, oleyl alcohol,polyoxyethylene sorbitan fatty acid esters and like suspension agents orsurfactants; solvents such as water, ethanol, 1-propanol, 2-propanol andthe like; isotonic agents such as sodium chloride and the like; pHadjusters such as sulfuric acid, hydrochloric acid and the like; etc.The kinds and amounts of additives can be suitably selected according tothe purpose of use.

The components and their proportions in the pharmaceutical compositionof the invention may be suitably selected according to the targeteddisease, age and gender of the patient, condition of the disease, etc.

For example, the pharmaceutical composition of the invention may containcarrageenan in an amount of about 0.001 to 10⁷ wt. % (preferably about0.01 to 10⁶ wt. %, more preferably about 0.1 to 10⁵ wt. %, particularlypreferably about 1 to 10⁴ wt. %), relative to the weight of thepharmacologically active substance. Additives may be incorporated in thecomposition in an amount of about 0 to 10⁷ wt. % (preferably about 0.5to 10⁶ wt. %, more preferably about 1 to 10⁴ wt. %, particularlypreferably about 10 to 10³ wt. %), relative to the weight of thepharmacologically active substance.

According to one preferred embodiment of the invention, thepharmaceutical composition contains carrageenan (particularlycarrageenan mainly comprising iota-carrageenan) in an amount of about0.01 to 10⁵ wt. % (preferably about 0.1 to 10⁴ wt. %), and additives(particularly water, ethanol, etc.) in an amount of about 0 to 10⁷ wt. %(preferably about 10 to 10⁶ wt. %), relative to the weight ofpharmacologically active substance (particularly β2 stimulants,antiasthmatic drugs and steroids).

According to a further preferred embodiment of the invention, thepharmaceutical composition contains iota-carrageenan in an amount ofabout 0.1 to 10⁴ wt. % (preferably about 1 to 10³ wt. %), and additives(particularly water, ethanol, etc.) in an amount of about 1 to 10⁶ wt. %(preferably about 10 to 10⁵ wt. %), relative to the weight ofpharmacologically active substance (particularly theophylline,procaterol, etc.).

According to another preferred embodiment of the invention, thepharmaceutical composition contains carrageenan (particularlycarrageenan mainly comprising iota-carrageenan) in an amount of about0.1 to 10⁴ wt. % (preferably about 1 to 10³ wt. %), relative to theweight of pharmacologically active substance (particularly β2stimulants, antiasthmatic drugs and steroids).

According to a further preferred embodiment of the invention, thepharmaceutical composition contains iota-carrageenan in an amount ofabout 0.1 to 10³ wt. % (preferably about 1 to 10² wt. %), relative tothe weight of pharmacologically active substance (particularlytheophylline, procaterol, etc.).

The pharmaceutical composition of the invention for pulmonaryadministration is usually used as an inhalant. The composition can beformed into dry powder inhalants, inhalant suspensions, inhalantsolutions, encapsulated inhalants and like known forms of inhalants.Such forms of inhalants can be prepared by filling the pharmaceuticalcomposition of the invention into an appropriate inhaler such as ametered-dose inhaler, dry powder inhaler, atomizer bottle, nebulizeretc. before use. Of the above forms of inhalants, powder inhalants areparticularly preferable.

When the pharmaceutical composition of the invention is used in the formof a powder, the mean particle diameter of the powder is not especiallylimited but, in view of the residence of the particles in the lungs, ispreferably in the range of about 0.1 to 20 μm, and particularly about 1to 5 μm. Although the particle size distribution of the powderpharmaceutical composition of the invention is not particularly limited,it is preferable that particles having a size of about 25 μm or moreaccount for not more than about 5% of the particles, and particularlypreferably 1% or less.

The pharmaceutical composition in the form of a powder of the inventioncan be produced by, for example, the drying-micronization method, thespray drying method and the like.

According to the drying-pulverization method, the pharmaceuticalcomposition in the form of a powder can be prepared by drying an aqueoussolution (or aqueous dispersion) containing a pharmacologically activesubstance and carrageenan and microparticulating the dried product.Stated more specifically, after dissolving (or dispersing) carrageenanin an aqueous medium, a pharmacologically active substance is added anddissolved (or dispersed) by stirring using a homogenizer, etc. to givean aqueous solution (or aqueous dispersion). The aqueous medium may bewater alone or a mixture of water and a lower alcohol. Examples ofusable lower alcohols include methanol, ethanol, 1-propanol, 2-propanoland like water-miscible alcohols. Ethanol is particularly preferable.After the obtained aqueous solution (or aqueous dispersion) is dried byblower, lyophilization, etc., the resulting product is pulverized ormicroparticulated into fine particles using jet mills, ball mills orlike devices to give a powder having the above mean particle diameter.If necessary, additives as mentioned above may be added in any of theabove steps.

According to the spray-drying method, the pharmaceutical composition inthe form of a powder of the invention can be prepared, for example, byspray-drying an aqueous solution (or aqueous dispersion) containing apharmacologically active substance and carrageenan formicroparticulation. The aqueous solution (or aqueous dispersion) can beprepared following the procedure of the above drying-micronizationmethod. The spray-drying process can be performed using a known method,thereby giving a powdery pharmaceutical composition in the form ofglobular particles with the above-mentioned mean particle diameter.

The inhalant suspensions, inhalant solutions, encapsulated inhalants,etc. can also be prepared using the pharmaceutical composition in theform of a powder produced by the drying-micronization method, thespray-drying method and the like, or by using carrageenan and apharmacologically active substance that can be administered via thelungs, according to known preparation methods.

Furthermore, the inhalant comprising the pharmaceutical composition ofthe invention is preferably used as an aerosol. The aerosol can beprepared, for example, by filling the pharmaceutical composition of theinvention and a propellant into an aerosol container. If necessary,dispersants, solvents and the like may be added. The aerosols may beprepared as 2-phase systems, 3-phase systems and diaphragm systems(double containers). The aerosol can be used in any form of a powder,suspension, solution or the like.

Examples of usable propellants include liquefied gas propellants,compressed gases and the like. Usable liquefied gas propellants include,for example, fluorinated hydrocarbons (e.g., CFC substitutes such asHCFC-22, HCFC-123, HFC-134a, HFC-227 and the like), liquefied petroleum,dimethyl ether and the like. Usable compressed gases include, forexample, soluble gases (e.g., carbon dioxide, nitrous oxide), insolublegases (e.g., nitrogen) and the like.

The dispersant and solvent may be suitably selected from the additivesmentioned above.

The aerosol can be prepared, for example, by a known 2-step methodcomprising the step of preparing the composition of the invention andthe step of filling and sealing the composition and propellant into theaerosol container.

As a preferred embodiment of the aerosol according to the invention, thefollowing aerosol can be mentioned: Examples of usable pharmacologicallyactive substances include procaterol, theophylline, steroids and saltsthereof (hydrochlorides, sulfates, etc.). Theophylline and procaterol(or hydrochlorides thereof) are particularly preferable. As carageenan,those mainly comprising iota-carrageenan are preferable. As propellants,fluorinated hydrocarbons such as HFC-134a, HFC-227 and like CFCsubstitutes are preferable. Examples of usable solvents include water,ethanol, 2-propanol and the like. Water and ethanol are particularlypreferable. In particular, a weight ratio of water to ethanol in therange of about 0:1 to 10:1 may be used.

The aerosol of the invention contains carrageenan in an amount of about0.01 to 10⁴ wt. % (preferably about 0.1 to 10³ wt. %), propellant in anamount of about 10² to 10⁷ wt. % (preferably about 10³ to 10⁶ wt. %),solvent in an amount of about 0 to 10⁶ wt. % (preferably about 10 to 10⁵wt. %), and dispersant in an amount of 0 to 10³ wt. % (preferably about0.01 to 10² wt. %), relative to the weight of pharmacologically activesubstance.

The pharmaceutical compositions of the invention are safe and effectivefor lung diseases and systemic diseases in mammals (e.g., humans, mice,rats, cats, dogs, sheep, horses, cows, monkeys) and can maintaintherapeutic effectiveness for a long time. The compositions can be used,for example, as anti-asthmatic agents, antiallergic agents, eosinophilchemotaxis inhibitors and preventive and therapeutic agents for diseasesassociated with eosinophilic infiltration (e.g., urticaria, atopicdermatitis, allergic rhinitis, hypersensitivity pneumonitis and likeallergic diseases, eczema, dermatitis herpetiformis, psoriasis and likeskin diseases, eosinophilic pneumonia (PIE syndrome), chronicobstructive pulmonary disease (COPD) and like respiratory diseases) andinfectious diseases caused by various bacteria. The compositions areparticularly useful as anti-asthmatic agents and preventive andtherapeutic agents for chronic obstructive pulmonary disease (COPD),hypersensitivity pneumonitis, eosinophilic pneumonia and influenza orlike infectious diseases.

Although the dosage of the pharmaceutical composition of the inventionmay vary depending on the type of pharmacologically active substance,the targeted disease, age, body weight, condition of the disease,administration route, number of administration times, etc., thecomposition is administered in an amount effective for allowing thepharmacologically active substance to exhibit its pharmacologicaleffects. For example, the composition is preferably administered suchthat the active ingredient (pharmacologically active substance) can begiven to a human adult in a dose of about 0.001 to about 100 mg, andgiven in a single dose or twice-four times a day.

The form of the pharmaceutical composition of the invention such as apowder, solution, suspension etc. may be suitably selected according tothe type of pharmacologically active substance, the targeted diseaseetc.

As an administration route, direct inhalation via the mouth using aninhaler is usually preferable.

Since the pharmaceutical composition of the invention allows directlocal administration into the airways, the pharmacologically activesubstances contained therein produce immediate effects. Furthermore, asit contains carrageenan, the composition enables the sustained releaseof the pharmacologically active substance in the lungs, and exhibitionof prolonged pharmacological effects. Therefore, when the pharmaceuticalcomposition of the invention is administered via the lungs, frequentadministration is unnecessary, and patient inconvenience is reduced. Inaddition, the administration of the minimum dose required can largelyreduce the risk of adverse side effects caused by massive drug doses.Thus the pharmaceutical composition of the invention can enhancetherapeutic effectiveness of the drug and reduce adverse side effects.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples are given below to illustrate the invention in more detail, butthe scope of the invention is not limited to these examples.

EXAMPLE 1

(1) 15 mg of procaterol hydrochloride (mean particle diameter 1.8 μm),(2) 100 mg of iota-carrageenan (product No. C-1138, produced by SigmaChemical Co. and sold by Sigma Aldrich Japan K.K.), (3) 87.90 g ofHFC-134a (product No. D10252125, produced and sold by Du Pont-MitsuiFluorochemicals Co., Ltd.), (4) 2.0 g of ethyl alcohol (99.5%), and (5)10.0 g of water were mixed in the following manner to give an inhalantsuspension.

First, the carrageenan was dissolved in water heated to about 80° C. andthe solution was cooled to about 40° C. After addition of the procaterolhydrochloride, the mixture was stirred using a homogenizer. Whilecooling the mixture at about −30° C., 20 g of HFC-134a was added withstirring and then the ethyl alcohol was added with stirring. HFC-134awas further added with stirring to make the total weight of the mixtureabout 100 g. A 9 g portion of the resulting mixture was filled into anaerosol container and the container was furnished with a metering valvefor releasing the aerosol in an amount of 50 μl each time.

EXAMPLE 2

1.0 g of iota-carrageenan (product No. C-1138, produced by SigmaChemical Co. and sold by Sigma Aldrich Japan K.K.) was dissolved in 100g of water heated to about 80° C. and the solution was cooled to about40° C. 20 g of theophylline was added and dissolved by stirring using ahomogenizer. The resulting solution was dried with a blower dryingmachine (SPHH-200, manufactured by Tabai Espec Corp.) and pulverized toabout 2 μm with a spiral jet mill (“50AS”, manufacture by HosokawaMicron Corp.). A 10-fold weight of lactose was added thereto and mixedusing a drum mixer to give an inhalant powder.

TEST EXAMPLE 1

The following four types of pharmaceutical solutions were prepared usingtheophylline as a pharmaceutically active compound. Solution B is acomposition of the invention, whereas solutions A, C and D arecomparative compositions.

Solution A: Theophylline was dissolved in isotonic phosphate buffer(PBS(−), Product No. 05913, manufactured by Nissui Pharmaceutical Co.,Ltd.) to give a 1 mg/ml theophylline solution A.

Solution B: Iota-carrageenan (product No. C-1138, produced by SigmaChemical Co. and sold by Sigma Aldrich Japan K.K.) was dissolved insolution A heated to about 80° C., and the resulting solution was cooledto room temperature to give a 1 w/v % (=10 mg/ml) iota-carrageenansolution B.

Solution C: Gelatin (product No. 16631-92, produced and sold by NacalaiTesque, Inc.) was dissolved in solution A heated to about 80° C., andthe resulting solution was cooled to room temperature to give a 5 w/v %gelatin solution C.

Solution D: Sodium alginate with a viscosity of 500-600 cP (product No.199-09961, manufactured by Wako Pure Chemical Industries, Ltd.) wasdissolved in solution A to give a 2 w/v % sodium alginate solution D.

Wistar male rats (body weight about 220 g) fasted for about 18 hourswere used as experimental animals. The intratracheal administration ofthe solutions was performed according to the method described inSchanker, L. S. et al., Am. J. Physiol., 222 (1972), p. 409. That is,the rats were anesthetized with pentobarbital (about 32 mg/kg) andsecured on their back on animal boards, the tracheas were exposedthrough a longitudinal incision. A section of polyethylene tube (i.d.1.5 mm, o.d. 2.3 mm) 2.5 cm in length was inserted through the trachealincision for a distance of 0.6 cm between the forth and fifth trachealrings caudal to the thyroid cartilage. Each of one hundred microlitersof drug solutions A-D was drawn into a glass microsyringe, and then ratwas maintained at an angle of 80°. The tip of syringe was insertedthrough the polyethylene tube to 1-2 mm above the bifurcation of thetrachea. Then, the solution was injected over a period of 1-2 sec. About45 sec after the administration, the rat was positioned at an angle of10° and the incision in the skin was then closed with suture.

After this operation, intravenous administration was performed byadministering 100 μl of solution A through the femoral vein.

0.2 ml of blood was collected from the subclavian vein at 15 sec., 30sec., 1 min., 2 min., 5 min., 10 min., 15 min, 30 min., 1 hr., 1.5 hr.,2 hr., 2.5 hr., 3 hr., 4 hr., 5 hr. and 6 hr. after the intratrachealand intravenous administrations and centrifuged at 1800 g for 10minutes. The theophylline concentrations in the obtained serum weremeasured by HPLC.

FIG. 1 shows the serum concentration-time profiles of theophylline afterintratracheal and intravenous administrations of solution A (n=4,mean±S.D.).

FIG. 2 shows the serum concentration-time profiles of theophylline afterintratracheal administration of solutions A to D (n=4, mean±S.D.).

Table 1 shows the mean pharmacokinetic parameters for the intratrachealadministration of solutions A to D at a dose of 100 μg/body (n=4). Theparameters in Table 1 indicate the following:

-   AUC_(6hr): Area under the serum theophylline concentration-time    curve to 6 hrs after administration (μg·hr/ml)-   AUC_(inf): Area under the serum theophylline concentration-time    curve to infinite time after administration (μg·hr/ml)-   C_(max): Maximum serum theophylline concentration (μg/ml)-   T_(max): Time required to reach maximum serum theophylline    concentration (hr)-   MRT_(inf): Mean residence time (calculated through infinite time    after administration) (hr)-   MAT_(inf): Mean absorption time (calculated through infinite time    after administration) (hr)

FIG. 1 shows that pulmonary absorption of theophylline was as quick andeffective as achieved by intravenous administration.

As is clear from FIG. 2 and Table 1, as compared with carrageenan-freesolution A (control), the serum theophylline concentration change afterthe intratracheal administration of 1 w/v % iota-carrageenan solution Bshows sustained release pharmacokinetic properties, i.e., a 5.5-foldincrease in time to reach the maximum serum theophylline concentration(T_(max)), 2.2-fold increase in mean residence time (MRT_(inf)),4.9-fold increase in mean absorption time (MAT_(inf)) and 40.2%suppression of the maximum concentration without reducing the area underthe serum concentration-time curves (AUC_(6hr), AUC_(inf)). Theseresults indicate that addition of 1 w/v % iota-carrageenan impartsvaluable sustained release properties, i.e., prolonged therapeuticeffects as demonstrated by maintenance of AUC_(6h) and AUC_(inf),reduced adverse side effects as demonstrated by suppression of C_(max),and increased effective serum theophylline concentration residence timeas demonstrated by increase of MRT_(inf) and MAT_(inf).

As compared with solution A, 5 w/v % gelatin solution C, whose sustainedrelease effect had been confirmed for 5(6)-carboxyfluorescein (CF)(molecular weight: 376), slightly suppressed C_(max) but no increase wasseen in T_(max), MRT_(inf) and MAT_(inf), and thus no sustained releaseeffects were observed.

Furthermore, 2 w/v % sodium alginate solution D, which has a viscositysimilar to 1 w/v % iota-carrageenan solution B, decreased AUC_(6h) andAUC_(inf) and also reduced MRT_(inf) and MAT_(inf). It is thus concludedthat the pulmonary sustained release effect of carrageenan is not basedon its viscosity but is carrageenan-specific. TABLE 1 Dose AUC_(6 hr)AUC_(inf) C_(max) T_(max) MRT_(inf) MAT_(inf) Solution (μg/body) (μg ·hr/mL) (μg · hr/mL) (μg/mL) (hr) (hr) (hr) A (Control) 100 2.89 4.023.96 0.0042 4.43 1.32 B (carrageenan) 100 3.96 8.33 1.59 0.023 9.55 6.44C (gelatin) 100 3.00 4.01 2.92 0.0042 4.29 1.18 D (sodium alginate) 1002.11 2.44 0.96 0.033 3.00 −0.11

By using carrageenan together with a pharmacologically active substance,the pharmaceutical composition of the invention can advantageouslycontrol the pulmonary absorption rate of the pharmacologically activesubstance and allow the substance to exhibit prolonged pharmacologicaleffects.

The publications mentioned in this specification are incorporated hereinby reference.

1. A sustained-release pharmaceutical composition for pulmonaryadministration comprising carrageenan and a pharmacologically activesubstance that can be administered via the lungs.
 2. A pharmaceuticalcomposition according to claim 1, wherein the carrageenan is at leastone member selected from the group consisting of kappa-carrageenan,iota-carrageenan and lambda-carrageenan.
 3. A pharmaceutical compositionaccording to claim 1, wherein the pharmacologically active substance isat least one member selected from the group consisting ofanticholinergic drugs, β2 stimulants, steroids, antiasthmatic drugs,antiallergic drugs, antiinflammatory drugs, antibacterial drugs,antifungal drugs, anti-influenza virus drugs, peptide drugs, antitumordrugs and vitamins.
 4. A pharmaceutical composition according to claim1, wherein carrageenan is present in an amount of about 0.001 to 10⁷ wt.% relative to the pharmacologically active substance.
 5. Apharmaceutical composition according to claim 1, wherein thepharmacologically active substance is one member selected from the groupconsisting of β2 stimulants, antiasthmatic drugs and steroids, andcarrageenan mainly comprising iota-carrageenan is present in an amountof about 0.01 to 10⁵ wt. % relative to the pharmacologically activesubstance.
 6. A pharmaceutical composition according to claim 1, whichis in the form of a powder having a mean particle diameter of about 0.1to 20 μm.
 7. A process for preparing a sustained release pharmaceuticalcomposition in the form of a powder for pulmonary administration, theprocess comprising drying an aqueous solution or aqueous dispersioncontaining a pharmacologically active substance that can be administeredvia the lungs and carrageenan, followed by pulverization, or comprisingspray drying the solution or dispersion.
 8. An inhalant comprising thepharmaceutical composition according to any one of claims 1 to
 6. 9. Anaerosol comprising the pharmaceutical composition according to any oneof claims 1 to 6, a propellant and an aerosol container.
 10. An aerosolaccording to claim 9, wherein relative to the pharmacologically activesubstance, carrageenan is present in an amount of about 0.01 to 10⁴ wt.%, and propellant is present in an amount of about 10² to 10⁷ wt. %. 11.An aerosol according to claim 9, which further comprises at least onemember selected from the group consisting of solvents and dispersants.12. An aerosol according to claim 11, wherein relative to thepharmacologically active substance, the solvent is present in an amountof about 0 to 10⁶ wt. %, and the dispersant is present in an amount ofabout 0 to 10³.
 13. A method for administering to a patient apharmacologically active substance that can be administered via thelungs, the method comprising administering an effective amount of apharmacologically active substance in combination with carrageenan tothe patient via the pulmonary route.
 14. A method for sustainedlyreleasing a pharmacologically active substance in the lungs, comprisingadministering via the lungs an effective amount of a pharmaceuticalcomposition containing the pharmacologically active substance andcarrageenan. 15-16. (canceled)